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ROAR: Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists

Sponsor
Leiden University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT05338632
Collaborator
U.S. Food and Drug Administration (FDA) (Other)
24
Enrollment
1
Location
4
Arms
21.5
Anticipated Duration (Months)
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intramuscular naloxone to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of opioid-induced respiratory depression from an opioid overdose in clinical practice and in the out-of-hospital overdose.

Condition or Disease Intervention/Treatment Phase
  • Drug: Narcan 40 MG/ML Nasal Spray
  • Drug: Naloxone Hydrochloride
 Phase 1

Detailed Description

Primary objective:

To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation and intranasal and intramuscular naloxone in its ability to reverse respiratory depression (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to perform simulation studies aimed at optimizing dosing regimens for intranasal and intramuscular naloxone in individuals that overdosed on potent opioids, with respiratory depression ranging from moderate to severe.

Secondary objectives:

To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intramuscular naloxone in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.

Study design:

This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.

Study population:

We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (> 60 daily oral morphine equivalents; 18-55 years).

Intervention:

Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intranasal naloxone (IN, 4 mg) will be administered at 30 min intervals. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.

Study 2: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intramuscular (IM, 2 mg) will be administered at 30 min intervals. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intramuscular bioavailability. At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.

Main study parameters:

The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone), ventilation is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below.

The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone), the pupil diameter is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

In this pharmacokinetic-pharmacodynamic modeling study, the effect of intramuscular and intranasal naloxone is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.

Respiratory depression is the topic of the current study; severe occurrences may be treated with intravenous naloxone. The participants will have no benefit from this trial in terms of disease burden reduction or disease alleviation. The gained knowledge from the study is large as this is the first study to systematically study IM and IN naloxone dosing in chronic opioid users.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
24 participants
Allocation:
Non-Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions
Anticipated Study Start Date :
Aug 16, 2022
Anticipated Primary Completion Date :
May 1, 2024
Anticipated Study Completion Date :
May 30, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Intravenous fentanyl year 1

continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.

Drug: Narcan 40 MG/ML Nasal Spray
naloxone 4mg/0.1 mL intranasal spray, up to 4 doses intranasally, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously
Other Names:
  • Intranasal naloxone

    		•
    Experimental: Intravenous sufentanil year 1

    continuous intravenous infusion of sufentanil to induce 40-60% respiratory depression.

    Drug: Narcan 40 MG/ML Nasal Spray
    naloxone 4mg/0.1 mL intranasal spray, up to 4 doses intranasally, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously
    Other Names:
  • Intranasal naloxone

    		•
    Experimental: Intravenous sufentanil year 2

    continuous intravenous infusion of sufentanil to induce 40-60% respiratory depression.

    Drug: Naloxone Hydrochloride
    naloxone 0.4mg/ml, up to 4 doses 2mg intramuscularly, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously
    Other Names:
  • Intramuscular naloxone

    		•
    Experimental: Intravenous fentanyl year 2

    continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.

    Drug: Naloxone Hydrochloride
    naloxone 0.4mg/ml, up to 4 doses 2mg intramuscularly, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously
    Other Names:
  • Intramuscular naloxone

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Minute ventilation [Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion]

      Minute ventilation (liters/minute)

    2. Plasma concentration sufentanil/fentanyl [at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone]

      50 samples of 2ml arterial blood

    3. Plasma concentration naloxone [at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone]

      50 samples of 2ml arterial blood

    Secondary Outcome Measures

    1. Pupil diameter [at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone. After discontinuation of infusion every 20 min. up to 6 hrs. following the start of opioid infusion]

      Pupil diameter in millimeters

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    Healthy volunteers

    1. Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;

    2. Male and female subjects, age 18 to 55 45 years, inclusive;

    3. Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug;

    4. Body Mass Index (BMI) 18 to 32 30 kg/m2, inclusive;

    5. Healthy as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, lab chemistry: estimated glomerular filtration rate >60 mL/min as estimated by the CKD-EPI equation, and AST or ALT levels < 3.0 times the upper limit of normal at screening, and negative serology tests for HIV, acute hepatitis B, or acute hepatitis C;

    6. No history of substance use disorder;

    7. No current use of any central nervous system (CNS) depressants prescribed or otherwise.

    Chronic opioid users

    1. Signed the consent form and able to comply with the requirements and restrictions listed therein;

    2. Males or females age 18 to 55 years, inclusive;

    3. Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 3 month after the last dose of study drug.

    4. BMI 18 to 32 kg/m2, inclusive;

    5. Opioid tolerant patients administered prescription opioids at daily doses ≥ 60 mg oral morphine equivalents (See Table 3);

    6. Stable as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, 12-lead ECG, hematology, and blood chemistry;

    7. No current use of any CNS depressants, besides opioids, prescribed or otherwise for 5 half-lives of the product before first study drug administration.

    Exclusion Criteria:

    Healthy volunteers

    1. Currently meet the criteria for diagnosis of substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria on any substance;

    2. Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;

    3. Consume, on average, >27 20 units/week of alcohol in men and > 20 13 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);

    4. Previous treatment with any prescribed medications or over-the-counter (OTC) medications (including homeopathic preparations, vitamins, and minerals) within 14 days or 5 half-lives (whichever is longer) prior to first study treatment administration;

    5. Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;

    6. Require on-going prescription or OTC medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]);

    7. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;

    8. History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;

    9. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;

    10. History or presence of allergic response to fentanyl, sufentanil or naloxone;

    11. Subjects who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial;

    12. Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;

    13. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;

    14. Require on-going prescription or over-the-counter medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]).

    Chronic opioid users

    1. Currently meet the criteria for diagnosis of moderate or severe substance use disorder according to the DSM-5 criteria on any substances other than opioids, caffeine, or nicotine;

    2. Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;

    3. Consume, on average, >27 units/week of alcohol in men and >20 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);

    4. Currently receiving medication-assisted treatment for the treatment of opioid-use disorder;

    5. Require on-going prescription or over-the-counter medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]);

    6. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;

    7. History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;

    8. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;

    9. History or presence of allergic response to study medication;

    10. Opioid tolerant patients who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial.

    11. Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI equation;

    12. Anemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;

    13. Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (OT patients with asymptomatic hepatitis B or C infection may be enrolled);

    14. AST or ALT levels >3.0 times the upper limit of normal at screening;

    15. Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;

    16. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Leiden University Medical Center Leiden ZH Netherlands 2333 ZA

    Sponsors and Collaborators

    • Leiden University Medical Center
    • U.S. Food and Drug Administration (FDA)

    Investigators

    • Principal Investigator: Rutger van der Schrier, MD, LUMC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Albert Dahan, Professor, Leiden University Medical Center
    ClinicalTrials.gov Identifier:
    NCT05338632
    Other Study ID Numbers:
    • P21.112
    First Posted:
    Apr 21, 2022
    Last Update Posted:
    Aug 16, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Albert Dahan, Professor, Leiden University Medical Center
    Reversal of opioid induced respiratory depression
    Intranasal naloxone
    Additional relevant MeSH terms:
    Respiratory Insufficiency
    Depression
    Depressive Disorder
    Naloxone

    Study Results

    No Results Posted as of Aug 16, 2022